PROJECT SUMMARY/ABSTRACT Chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus that causes explosive epidemics of a severe febrile illness characterized by debilitating polyarthralgia in humans. CHIKV caused an estimated 1.3 million new cases in India alone in 2006, and has the potential to spread globally because of the distribution and abundance of its mosquito vectors, Aedes aegypti and Aedes albopictus. During recent outbreaks more severe forms of CHIKV were observed, including encephalopathy and hemorrhagic fever, suggesting the emergence of more virulent strains. Closer to the US, in 2013-14 CHIKV has infected over 1.5 million people in South America and on multiple island nations of the Caribbean. Currently, no specific treatment or vaccine is available. Given its global burden, the increased travel into CHIKV-endemic areas, and the worldwide spread of its mosquito vector, there is a pressing need for the development of therapeutic agents and vaccines against CHIKV. Therefore, in order to reduce the impact of this virus and the devastating polyarthralgia that it causes, we must develop new therapies and vaccines to treat persistent CHIKV infections. The goal of this project is to evaluate and optimize immunogenicity and protection of novel dendritic cell-targeting Adenovirus CHIKV- vaccines in animal models of CHIKV infection. We will utilize our highly innovative DC-targeting strategy in conjunction with a simian Adenoviral backbone to circumvent prior immunity to human Adenoviruses. Development of this highly tractable vaccine platform is critical for its use for vaccination against other pathogens and cancer.